The present invention relates to new N-mercaptoacyl amino acid compounds, to a process for their preparation and to pharmaceutical compositions containing them.
Numerous patent applications describe amino acid compounds for use as inhibitors of neutral endopeptidase (NEP) (EP 449 523), as inhibitors of endothelin converting enzyme (ECE) (WO 97/32874), or as mixed inhibitors of NEP and angiotensin I converting enzyme (ACE).
The pharmacological role played by those enzymes is:
for ACE, to convert angiotensin I to angiotensin II and to degrade bradykinin to inactive peptides,
for NEP, to degrade bradykinin and atrial natriuretic peptide to inactive peptides,
for ECE, to convert big endothelin-1 to endothelin-1.
Angiotensin II, endothelin, bradykinin and atrial natriuretic peptide are the most important peptides hitherto implicated in regulating vascular tone, cardiovascular re-modelling and hydroelectrolytic homeostasis. Their metabolism is essentially controlled by those three enzymes. The inhibition of one and/or the other of those enzymes enables optimum peptidergic balance to be restored by favouring vasodilatory, antitrophic and natriuretic peptides (bradykinin, atrial natriuretic peptide) over vasoconstrictive, trophic and anti-natriuretic peptides (angiotensin II, endothelin-1), hence the cardiovascular therapeutic benefit.
The pharmacological properties of the mixed ACE/NEP inhibitors described in the prior art overlook the major cardiovascular role of the endothelin system (Haynes W. G. et al., Journal of Hypertension, 1998, 16 (8), pp. 1081-1098) and the demonstrated implication of NEP in the degradation of endothelin-1 (Vijayaraghavan J. et al., J. Biol. Chem., 1990, 265, pp. 14150-14155). Thus, treatment with mixed ACE/NEP inhibitors results in an increase in levels of endothelin-1 which, in the long term, can have an adverse effect on the expected therapeutic benefit. This problem is solved by obtaining the three types of inhibition within the same molecule, enabling counter-regulation of that activation and so bringing about sustained strengthened therapeutic efficacy. The development of molecules that inhibit those three enzymes thus constitutes a very significant advance in the treatment of arterial hypertension and cardiovascular diseases.
The compounds of the present invention are new and are excellent triple inhibitors, that is to say they are capable of inhibiting NEP, ACE and ECE simultaneously.
The present invention relates more especially to compounds of formula (I): 
wherein:
n represents an integer wherein 0xe2x89xa6nxe2x89xa63,
m represents an integer wherein 0xe2x89xa6mxe2x89xa66,
R3 and R4 together form, with the two carbon atoms carrying them, a phenyl group that is unsubstituted or substituted by from 1 to 3 identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl, aryl, heteroaryl and halogen atoms,
B represents a heteroaryl group,
R2 represents a hydrogen atom or an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, arylalkyl or aroyl group,
R1 represents a hydrogen atom, an acyl, aroyl or cycloalkylcarbonyl group or a group of formula (II): 
wherein m, n, R2, R3, R4 and B are as defined hereinbefore,
it being understood that:
xe2x80x9calkylxe2x80x9d is understood to mean an alkyl group having a linear or branched chain containing from 1 to 6 carbon atoms,
xe2x80x9calkenylxe2x80x9d is understood to mean an alkyl group containing from 2 to 6 carbon atoms and one or more double bonds,
xe2x80x9calkynylxe2x80x9d is understood to mean an alkyl group containing from 2 to 6 carbon atoms and one or more triple bonds,
xe2x80x9ccycloalkylxe2x80x9d is understood to mean a cyclic alkyl group containing from 3 to 8 carbon atoms,
xe2x80x9cacylxe2x80x9d is understood to mean an RCO group wherein R represents an alkyl group as defined hereinbefore,
it being possible for the groups xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d to be substituted by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino and halogen atoms,
and it being possible for the groups xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkylalkylxe2x80x9d to be substituted on the cyclic moiety by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl or naphthyl group unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean any mono- or poly-cyclic aromatic group containing from 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, those groups being unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl and halogen atoms, it being possible for the polycyclic groups also to be partially or completely hydrogenated on one of the rings,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (I) wherein R1 represents a hydrogen atom or an acyl group.
The preferred value for m and n is 1.
The preferred R2 groups are the hydrogen atom and the groups alkyl and arylalkyl.
Advantageously, the invention relates to compounds of formula (I) wherein R3 and R4 together form, with the two carbon atoms carrying them, a substituted phenyl group.
More advantageously, the invention relates to compounds of formula (I) wherein R3 and R4 together form, with the two carbon atoms carrying them, a phenyl group substituted by a halogen atom and more especially by a bromine atom or substituted by an alkoxy or alkylthio group and more especially by the groups methoxy and methylthio.
More advantageously still, the invention relates to compounds of formula (I) substituted in the 2-position by an indane group substituted in the 5-position by a halogen atom and more especially by a bromine atom or by an alkoxy group and more especially by a methoxy group.
The preferred B groups are heteroaryls containing an NH group, such as, for example, the groups indolyl, imidazolyl, pyrrolopyridinyl, pyrroloquinolinyl, pyrrolyl and pyrrolopyrazinyl, more especially the groups indolyl, 1H-pyrrolo[2,3-b]pyridine and 1H-pyrrolo[3,2-h]quinolinyl.
The preferred configuration of the compounds of formula (I) is 2S-3R, and more especially 2S-3R-4S.
More advantageously still, the invention relates to:
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan (2S-3R4S),
N-[2-(5-chloro-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[(2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[3-mercapto-2-(1,2,3,4-tetrahydro-1-naphthalenyl)propanoyl]tryptophan,
N-[2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(4-methoxy-2,3-dihydro-1Hinden-1-yl) 3-mercaptopropanoyl]tryptophan,
N-[2-(5-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-{2-[5-(methylthio)-2,3-dihydro-1H-inden-1-yl]-3-mercaptopropanoyl}tryptophan,
N-[2-(5-cyano-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo-[2,3-b]pyridin-3-yl)alanine,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo-[2,3-b]pyridin-3-yl)alanine (2S-3R-4S),
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-11-methyltryptophan,
3-(1-benzothiophen-3-yl)-N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]alanine,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(3-pyridinyl)alanine,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(2-quinolinyl)alanine,
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-5-methoxytryptophan (2S-3R-4S),
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-5-fluorotryptophan (2S-3R-4S),
N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo[3,2-h]-quinolin-3-yl)alanine (2S-3R-4S).
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (III): 
wherein R3, R4 and n are as defined for formula (I),
which is subjected to the action of a reducing agent, such as NaBH4 for example, to obtain a compound of formula (IV): 
wherein n, R3 and R4 are as defined hereinbefore,
which is converted with a halogenating agent, such as Me3SiBr for example, to the corresponding halogen compound of formula (V): 
wherein R3, R4 and n are as defined hereinbefore,
which is condensed, in a basic medium, with ethyl 2-(diethoxyphosphoryl)acetate to yield a compound of formula (VI): 
wherein R3, R4 and n are as defined hereinbefore,
which is reacted with formaldehyde in a basic medium to obtain a compound of formula (VII): 
wherein R3, R4 and n are as defined hereinbefore,
which is hydrolysed in the presence of sodium hydroxide to yield a compound of formula (VIII): 
wherein R3, R4 and n are as defined hereinbefore,
which is condensed with a compound of formula (IX): 
wherein Rxe2x80x21 represents an alkyl, aryl or cycloalkyl group,
to obtain a compound of formula (X): 
wherein R3, R4, Rxe2x80x21 and n are as defined hereinbefore,
which is condensed, in the presence of a coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide for example, with a compound of formula (XI): 
wherein B and m are as defined for formula (I), and R12 represents an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, acyl, arylalkyl or aroyl group,
to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein Rxe2x80x21, R3, R4, Rxe2x80x22, m, n and B are as defined hereinbefore,
which may be partially or completely hydrolysed in a basic medium to yield a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein R3, R4, m, n and B are as defined hereinbefore, Rxe2x80x31 represents a group Rxe2x80x21 or a hydrogen atom, and Rxe2x80x32 represents a group Rxe2x80x22 or a hydrogen atom, with the proviso that at least one of the groups Rxe2x80x31 and Rxe2x80x32 represents a hydrogen atom,
which compound of formula (I/b), when Rxe2x80x31 represents a hydrogen atom, may be placed in an oxidising medium to obtain a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein R2, R3, R4, m, n and B are as defined hereinbefore, and Rxe2x80x2xe2x80x31 represents a group of formula (II),
which compounds of formulae (I/a) to (I/c) constitute the totality of the compounds of the invention, and may be purified in accordance with a conventional separation technique, are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base, and which are separated, where appropriate, into their isomers in accordance with a conventional separation technique.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (X) as defined hereinbefore, the diastereoisomers of which are separated by chromatography to yield the compounds of formulae (Xa) and (Xb): 
wherein Rxe2x80x21, R3, R4 and n are as defined hereinbefore,
with which compound of formula (Xb) it is possible to form a salt with a chiral amine, such as (R)-(+)-xcex1-methylbenzylamine for example, to yield, after resolution by successive recrystallisation operations, a compound of formula (Xbxe2x80x2) 
wherein Rxe2x80x21, R3, R4 and n are as defined hereinbefore,
which is condensed, in the presence of a coupling agent such as EDCI, with a compound of formula (XIa): 
wherein Rxe2x80x22, m and B are as defined hereinbefore,
to obtain a compound of formula (I/axe2x80x2), a particular case of the compounds of formula (I/a): 
wherein Rxe2x80x21, Rxe2x80x22, R3, R4, m, n and B are as defined hereinbefore,
the diastereoisomers (2R, 3S), (2R, 3R) and (2S, 3R) being obtained analogously starting from the corresponding compounds (Xa) and (Xb),
it also being possible to obtain those compounds by condensing a compound of formula (XIa) with a compound of formula (Xa) or (Xb) followed by separation by chromatography.
The compounds of formula (III) are either commercially available or are readily accessible to the person skilled in the art by conventional chemical reactions.
The compounds of the present invention have very valuable pharmacological properties since they enable simultaneous inhibition of:
angiotensin I converting enzyme (ACE), which is responsible for converting angiotensin I into angiotensin II and for degrading bradykinin into inactive peptides,
neutral endopeptidase (NEP), which is responsible for degrading bradykinin and atrial natriuretic peptide into inactive peptides, and
endothelin converting enzyme (ECE), which is responsible for converting big endothelin-1 into endothelin-1.
Those enzymes play a crucial role in establishing the proportions between vasodilatory, antitrophic and natriuretic peptides on the one hand (bradykinin, atrial natriuretic peptide) and vasoconstrictive, trophic and anti-natriuretic peptides on the other hand (angiotensin II, endothelin 1).
Moreover, it has recently been shown that neutral endopeptidase is implicated in the mechanisms of degradation of endothelin-1. The inhibition of one and/or the other of those enzymes makes it possible to modulate that peptidergic balance.
The numerous mixed ACE/NEP inhibitors described in the literature thus increase the proportion of vasodilatory peptides over vasoconstrictive peptides. Nonetheless, this approach overlooks the role played by the endothelin system, which is all the more harmful because those mixed inhibitors, by inhibiting NEP, increase the levels of endothelin-1, which translates into a reduction in the expected therapeutic benefit.
Triple inhibition avoids the accumulation of endothelin-1, and thus results in sustained strengthened therapeutic efficacy, and in a broadening of the spectrum of activity of the compounds.
Those properties mean that they can be used therapeutically in the treatment of arterial hypertension including pulmonary arterial hypertension, myocardial ischaemia, angina pectoris, cardiac insufficiency, vasculopathies including diabetic vasculopathies, atherosclerosis and post-angioplasty restenosis, acute or chronic renal insufficiency, cerebrovascular diseases including stroke and sub-arachnoidal haemorrhage, peripheral ischaemia, and toxicity to cyclosporin.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration and, for example, tablets or dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, and any associated treatments and ranges from 0.1 mg to 1 g per 24 hours in one or more administrations.
The following Examples illustrate the invention and do not limit it in any way. The following Preparations yield compounds of the invention or synthesis intermediates for use in the preparation of the invention.
Preparation 1: 5-Bromo-1-indanone
Step A: 1-(4-Bromophenyl)-3-chloro-1-propanone
45.3 g of aluminium chloride are stirred at room temperature in 80 ml of CH2Cl2. Maintaining vigorous stirring, a solution of xcex2-propionic acid chloride (38.09 g, 28.7 ml, 0.3 mol) is poured slowly into 20 ml of CH2Cl2. The CH2Cl2-AlCl3-acid chloride complex forms quickly and the solution turns dark red. A solution of bromobenzene (47.1 g, 31.6 ml, 0.3 mol) is then introduced dropwise into 20 ml of CH2Cl2. The solution is then stirred for 15 hours at room temperature. The mixture is hydrolysed over 190 g of ice, to which 7.6 ml of concentrated acetic acid have been added. The organic phase is washed neutral and the solvent is removed by evaporation under reduced pressure. A dark red oil is obtained, from which the title compound is obtained in the form of a yellowish solid by extraction while hot with petroleum ether.
Melting point: 60-61xc2x0 C.
Step B: 5-Bromo-1-indanone
A mixture of 448 g of AlCl3 (335.98 mmol) and 112 g of NaCl is brought to 180xc2x0 C. in a reactor. The mixture is stirred whilst introducing the compound obtained in Step A (44.77 g, 180.9 mmol) slowly using a spatula. The temperature is maintained at 180-220xc2x0 C. The reaction continues for 30 minutes. Hydrolysis over 4.5 kg of ice in the presence of 135 ml of acetic acid yields a dark brown precipitate, which is filtered off, washed with water and dried in vacuo. The title compound is isolated by recrystallisation from methanol.
Melting point: 126-127xc2x0 C.
Preparation 2: 1-Oxo-5-indanecarbonitrile
A mixture of 5 g of the compound obtained in Preparation 1 (23 mmol) and 2.65 g of CuCN in 6 ml of DMF is refluxed under argon. After stirring at 120xc2x0 C. for 15 hours, the mixture is added to a solution of 11.2 g of FeCl3 in 35 ml of water and 6 ml of concentrated hydrochloric acid. The mixture is maintained at 60-71xc2x0 C. for 15 minutes. The mixture is extracted with 3xc3x9720 ml of 10% NaHCO3, dried over Na2SO4 and concentrated in vacuo to yield the title compound in the form of a slightly yellow solid.
Melting point: 129-130xc2x0 C.
Preparation 3: 5-(Methylthio)-1-indanone
1.27 g of CH3SNa (18.13 mmol; 1.2 eq.) are placed in 30 ml of DMF at 0xc2x0 C. The compound obtained in Preparation 1 (3.19 g; 15.11 mmol) is introduced and the mixture is stirred at room temperature for 3 hours. The reaction mixture is then poured into 150 ml of water and extracted with AcOEt. The organic phase is dried over Na2SO4 and concentrated in vacuo to yield the title compound in the form of a brownish crystalline product. Melting point: 99-102xc2x0 C.
Preparation 4: 5-Hydroxy-1-indanone
5 g of 5-methoxy-1-indanone (30.9 mmol) are added under argon to a suspension of 10.31 g of aluminium chloride in 150 ml of anhydrous toluene. The suspension is stirred vigorously whilst being brought to reflux. After reacting for 30 minutes, the mixture is left to return to room temperature, and 30 g of ice are added. The organic phase is separated off. The aqueous phase is washed with 2xc3x9730 ml of ethyl acetate. The organic phases are combined, washed with 4xc3x9750 ml of water, dried over Na2SO4 and concentrated in vacuo to yield the title compound in the form of a slightly brown solid.
Melting point: 183xc2x0 C.
Preparation 5: 5-Ethoxy-1-indanone
3 g of the compound obtained in Preparation 4 (20.2 mmol), 5 ml of ethyl iodide and 8.4 g of potassium carbonate in 200 ml of acetone are refluxed with stirring. After reacting for three hours, the suspension is filtered, and the precipitate is washed with acetone. The acetone is eliminated under reduced pressure. The solid residue is taken up in 25 ml of chloroform, washed with 2xc3x9710 ml of water, predried with a saturated sodium chloride solution, filtered over Na2SO4, and concentrated in vacuo. The title compound is obtained in the form of a slightly orange solid.
Melting point: 82-83xc2x0 C.
Preparation 6: 5-Chloro-1-indanone
The procedure is as for Preparation 1 starting from chlorobenzene.
Preparation 7: 5-(Dimethylamino)-1-indanone
Step A: N-(2,3-Dihydro-1H-inden-5-yl)acetamide
A mixture of 70 ml of acetic anhydride and 15 g of sodium acetate is added dropwise, with stirring, to 50 g of-5-aminoindane. At the end of the exothermic reaction, the solution is heated at 100xc2x0 C. for one hour. The solution is then poured into 500 g of ice; a precipitate is observed to form, which is collected by filtration and taken up in 400 ml of ethyl acetate. The solution is washed with 2xc3x97250 ml of water, 2xc3x97200 ml of a 20% sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The title compound is obtained in the form of a yellow solid.
Melting point: 105-106xc2x0 C.
Step B: N-(1-Oxo-2,3-dihydro-1H-inden-5-yl)acetamide
A solution of 50 g of chromium trioxide dissolved in a mixture of 35 ml of water and 150 ml of acetic acid is added dropwise, with stirring, to 62 g of the compound obtained in Step A in a mixture of 175 ml of acetic acid and 50 ml of acetic anhydride in such a manner that the reaction mixture remains at a temperature below 10xc2x0 C. After a night at room temperature, the solution is poured into 1 liter of ice-cold water. A precipitate is observed to form, which is collected by filtration. The precipitate is washed with water until neutral and then dried in a dessicator to yield the title compound in the form of a yellow solid.
Melting point: 172xc2x0 C.
Step C: 5-Amino-1-indanone
47 g of the compound obtained in Step B dissolved in 700 ml of 1.5N hydrochloric acid are brought to reflux. After reacting for one hour, the starting material having passed completely into solution, the solution is left to return to room temperature. The reaction mixture is poured into 800 ml of a 2M sodium hydroxide solution. The precipitate is filtered off and washed with water until neutral to yield the title compound in the form of a yellow solid.
Melting point: 184xc2x0 C.
Step D: 5-(Dimethylamino)-1-indanone
5 g of the compound obtained in Step C (20.2 mmol), 8.1 ml of methyl iodide and 7.2 g of sodium carbonate in 30 ml of acetone are brought to reflux with stirring. After one night, the solvent is removed in vacuo, yielding a solid which is taken up in a mixture of 100 ml of ethyl acetate and 50 ml of water. The organic phase is separated off, washed with 4xc3x9750 ml of water, and then with 50 ml of a saturated sodium chloride solution, dried over Na2SO4, and concentrated in vacuo. A slightly orange crystalline product is obtained, which is purified by chromatography over neutral alumina.
Melting point: 16xc2x0 C.